Identifying Metabolic Signatures of Bisphenol Analog Exposure: Implication for Rapid Toxicity Screening of New Alternatives

The lack of toxicity assessments for bisphenol A substitutes (BPs) has resulted in a vicious circle of pollution, replacement, and repollution. Herein, we aimed to develop specific biomarkers for rapid toxic screening and evaluation. We investigated the effects of BPs exposure on 16 health indicators of liver function, kidney function, and metabolic indices. Using nontargeted and targeted metabolomics, we systematically profiled plasma metabolite alterations to elucidate potential metabolic disruptions, toxic mechanisms, and metabolic signatures. Molecular docking was used to examine the binding activity of BPs and their metabolic transformation products (MTPs) with hormone receptors, revealing potential links between biotransformation and metabolic disruption. We found that metabolic indices like cholesterol were vulnerable to BPs exposure. Exposure to bisphenol AF (BPAF), BPB, and BPAP significantly altered 554, 391, and 236 metabolites, respectively, with kynurenine and histidine identified as common metabolic signatures. Histidine/kynurenine ratio (AUC: 0.937, ACC: 0.820) exhibited superior predictive ability for distinguishing BPs exposure compared to either histidine or kynurenine alone, serving as promising biomarkers for rapid toxic evaluation of emerging BPs. Interestingly, increased formation of MTPs with weaker hormone receptor binding reduced metabolic interference, suggesting that the metabolic disruption of BPs depends on their metabolic detoxification capacity.